Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (K. D. Bhoola et al., “Kallikrein-Kinin Cascade”, Encyclopedia of Respiratory Medicine, 483-493; J. W. Bryant et al., “Human plasma kallikrein-kinin system: physiological and biochemical parameters” Cardiovascular and haematological agents in medicinal chemistry, 7, 234-250, 2009; K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, “Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides”, Brazilian Journal of Medical and Biological Research 2000, 33, 665-677). It is an essential member of the intrinsic blood coagulation cascade, although its role in this cascade does not involve the release of bradykinin or enzymatic cleavage. Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekallikrein that circulates in plasma as a heterodimer complex bound to high molecular weight kininogen which is activated to give the active plasma kallikrein. Kinins are potent mediators of inflammation that act through G protein-coupled receptors and antagonists of kinins (such as bradykinin antagonists, for example icatibant) have previously been investigated as potential therapeutic agents for the treatment of a number of disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).
Plasma kallikrein is thought to play a role in a number of inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients who present with a genetic deficiency in C1 esterase inhibitor suffer from hereditary angioedema (HAE), which results in intermittent swelling of face, hands, throat, gastro-intestinal tract and genitals. Blisters formed during acute episodes contain high levels of plasma kallikrein which cleaves high molecular weight kininogen liberating bradykinin, thereby leading to increased vascular permeability. Treatment with a large protein plasma kallikrein inhibitor has been shown to treat HAE effectively by preventing the release of bradykinin, which causes increased vascular permeability (A. Lehmann “Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery” Expert Opin. Biol. Ther. 8, 1187-99).
The plasma kallikrein-kinin system is a system of blood proteins that plays a role in inflammation, blood pressure control, coagulation and pain. The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular oedema. It has recently been discovered that plasma kallikrein contributes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. “Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats” Diabetes, 2011, 60, 1590-98). Furthermore, administration of the plasma kallikrein inhibitor ASP-440 ameliorated both retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore, a plasma kallikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular oedema. Other complications of diabetes such as cerebral haemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which have associations with plasma kallikrein may also be considered as targets for a plasma kallikrein inhibitor.
Synthetic and small molecule plasma kallikrein inhibitors have been described, for example by Garrett et al. (“Peptide aldehyde . . . ” J. Peptide Res. 52, 62-71 (1998)), T. Griesbacher et al. (“Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats” British Journal of Pharmacology 137, 692-700 (2002)), Evans (“Selective dipeptide inhibitors of kallikrein” WO03/076458), Szelke et al. (“Kininogenase inhibitors” WO92/04371), D. M. Evans et al. (Immunolpharmacology, 32, 115-116 (1996)), Szelke et al. (“Kininogen inhibitors” WO95/07921), Antonsson et al. (“New peptides derivatives” WO94/29335), J. Corte et al. (“Six membered heterocycles useful as serine protease inhibitors” WO2005/123680), J. Stürzbecher et al. (Brazilian J. Med. Biol. Res 27, 1929-34 (1994)), Kettner et al. (U.S. Pat. No. 5,187,157), N. Teno et al. (Chem. Pharm. Bull. 41, 1079-1090 (1993)), W. B. Young et al. (“Small molecule inhibitors of plasma kallikrein” Bioorg. Med. Chem. Letts. 16, 2034-2036 (2006)), Okada et al. (“Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship” Chem. Pharm. Bull. 48, 1964-72 (2000)), Steinmetzer et al. (“Trypsin-like serine protease inhibitors and their preparation and use” WO08/049595), Zhang et al. (“Discovery of highly potent small molecule kallikrein inhibitors” Medicinal Chemistry 2, 545-553 (2006)), Sinha et al. (“Inhibitors of plasma kallikrein” WO08/016883), Evans et al. (“Benzylamine derivatives as inhibitors of plasma kallikrein” WO2013/005045), Brandl et al. (“N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein” WO2012/017020), Shigenaga et al. (“Plasma Kallikrein Inhibitors” WO2011/118672), and Kolte et al. (“Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor”, British Journal of Pharmacology (2011), 162(7), 1639-1649). Also, Steinmetzer et al. (“Serine protease inhibitors” WO2012/004678) describes cyclized peptide analogs which are inhibitors of human plasmin and plasma kallikrein.
To date, the only selective plasma kallikrein inhibitor approved for medical use is Ecallantide. Ecallantide is formulated as a solution for injection. It is a large protein plasma kallikrein inhibitor that presents a risk of anaphylactic reactions. Other plasma kallikrein inhibitors known in the art are generally small molecules that usually include highly polar and ionisable functional groups, such as guanidines or amidines. It is well known that such functional groups impart a high degree of aqueous solubility to the compound. However, it is also well known that highly polar and ionisable guanidine or amidine functionalities may be limiting to gut permeability and therefore to oral availability (see, for example, “Small Molecule Anticoagulant/Antithrombotic Agents” Annual Reports in Medicinal Chemistry, Volume 40, 2005, Pages 85-101 Robert M. Scarborough, Anj ali Pandey, Xiaoming Zhang and Tamie J. Chilcote and Sukanto Sinha, “ASP-634: An Oral Drug Candidate for Diabetic Macular Edema”, ARVO 2012 May 6-May 9, 2012, Fort Lauderdale, Fla., Presentation 2240). It is further reported that oral absorption may be improved by creating a prodrug such as ASP-634. However, it is well known that prodrugs can suffer from several drawbacks, for example, poor chemical stability and potential toxicity from the inert carrier or from unexpected metabolites.
Ionisable functional groups provide water solubility but, as a rule, water soluble small molecules are rapidly cleared, for example from the vitreous (see “Review: Practical Issues in Intravitreal Drug Delivery”, Journal of Ocular Pharmacology and Therapeutics, Volume 17, Number 4, 2001, page 393-401, David Maurice). Also, solubilised drugs are susceptible to degradation. It is an aim of the present invention to identify compounds that lack polar or ionisable groups, for example compounds with a pKa less than 11, which are sparingly soluble, and that would enable formulation of serine protease inhibitors as aqueous suspensions thus providing extended duration of the exposure and an extended shelf life.
There are only few reports of plasma kallikrein inhibitors that do not feature guanidine or amidine functionalities. For example Brandl et al. (“N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein” WO2012/017020) and Evans et al. (“Benzylamine derivatives as inhibitors of plasma kallikrein” WO2013/005045). Brandl discloses plasma kallikrein inhibitors that include an amino-pyridine functionality. Oral efficacy in a rat model is demonstrated for one example at relatively high doses of 30 mg/kg and 100 mg/kg but the pharmacokinetic profile is not reported. Thus it is not yet known whether such compounds will provide sufficient oral availability for progression to the clinic. Evans discloses plasma kallikrein inhibitors that feature a benzylamine functionality. Pharmacokinetic data is presented for one example following intravitreous administration to rabbits. However, the disclosed data is limited to only 7 days post dosing; no data past this time point is described. Evans further discloses thermodynamic solubility data that demonstrate that the inhibitors are very slightly soluble, practically insoluble or insoluble (less than 1 mg/mL in phosphate buffer).
Intravenous administration of drugs is known in the art, and is particularly useful in treating life threatening conditions in view of the almost immediate effect on a subject following administration. However, there is a risk that intravenous administration of compositions that contain drugs that are poorly soluble in water may effect precipitation in vivo, which could cause serious adverse side-effects or death. The use of stabilizing agents to mitigate the risk of precipitation is known in the art. However, the amount of stabilizing agent may need to be excessive in compositions that contain poorly soluble drugs thus causing adverse side-effects, and so their use is suboptimal. There is therefore a need for compositions which can be administered safely without the risk of serious adverse side-effects.
Triesence® is a suspension of triamcinolone, a corticosteroid, for intravitreal injection. Triesence® is indicated for the treatment of ophthalmic diseases: sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids. However, the complexity of ophthalmic disorders suggests there is a need for pharmacologic agents with modes of action distinguishable from corticosteroids. Plasma kallikrein inhibitors could fulfil this need.
It is an object of the present invention to provide a composition of a poorly soluble plasma kallikrein inhibitor that may be administered parenterally. In the present application, the aforesaid plasma kallikrein inhibitor hereinafter refers to a compound of formula I as defined below.
Intravitreal administration of the compositions of the present invention results in slow elimination of the active ingredient from the vitreous humor. Moreover, high concentrations of the active ingredient in the retina (with choroid) are observed, which confirms that the active ingredient reaches the posterior ocular tissues.
It is therefore a further object of the invention to provide a composition with improved patient compliance, by reducing the frequency at which the composition needs to be administered to a subject.